Quaternary ammonium salts



Patented June 9, 1953 UNITED STAT ES PATENT OFFICE 2,641,610 QUATERNARY AMMONIUM SALTS Harry James Barber, Dagenham, England, as signor to' May & .Baker Limited, Dagenham, England, a British company.

No Drawing. Application October: 18,. 1951, Se-

rial No. 252,003. In Great Britain October 27,

Where R represents a methyl or ethyl group and X represents the residue of an acid. These salts are readily soluble in water and their manufacture in the pure statewith good yield is com plicated by the difiiculty experienced in the removal ofsoluble by-products.

It is the object of the present invention to provide new intermediates from which the above bis-quaternary ammonium salts can readily be prepared in a good yield on a commercial scale.

These new intermediates are salts of the foregoing type in which the groups X are replaced by the radical of 2 Z-dihydroxy-l l-dinaphthyl-methane-3z3-dicarboxyli'c' acid (hereinafter in. this specification and in the appended claims this acid is, for convenience, called embonic acid while its salts. are hereinafter called embonates). While embonic acid does not form s Clainis (cram-501) readily separable salts with quaternary ammonium derivatives such as tetraethyl ammonium or polymethylene bis-quaternary ammoniums containing less than six methylene groups it has been found that the embonates referred to above may be very simplyprepared in a pure state.

According to the present invention, these new embonates are obtained through the double-decomposition in aqueous solution of a corresponding bis-quaternary ammonium salt of the aforesaid type by adding to that solution 'a watersoluble embonate.

The new embonates are very sparingly soluble in water at normal temperatures although they will form solutions of reasonable concentration at elevated temperature. It is, therefore, asimple matter to isolate the new embonates from aqueous solutions in which they are prepared. Since embonic acid itself is substantially insoluble in water even at boiling point the new embonates provide a convenient and simple route to the more soluble corresponding bis-quaternary salts uncontaminated by soluble by-products. Thus embonic acid is precipitated by acidification of a quaternary ammonium embonate leaving the quaternary ammonium salt of the acidifying agent in solution in a substantially pure state.

It will be appreciated that the process of the presentinvention can be regardedas a step in .the production of bis-quaternary ammonium salts of the. aforesaid general formula in which X represents an anion. of an acid other than embonic acid and which are more' soluble' in waterthan the corresponding embonate. the new embonates will be directly isolated from aqueous solution containing oneof such salts (for example, sulphate, nitrate, halideor sulphonate) by the addition thereto of a watersoluble embonate such as sodium embonate. In the case,. especially, of the quaternary ammonium saltsof the aforesaid general formula in which R. represents. methyl this fact is of considerable commercial importance as will now be explained. Of the theoretically suitable hexamethylene intermediates for the production of these particular quaternary ammonium salts, hexamethylene diamine is to be preferred from the viewpoint of accessibility. Theoretically, this compound could be directly methylated and quaternated in a single operation using, for ex ample, dimethyl sulphate or other reactive methyl ester such as a halide but in actual practice this was hitherto'found to possess serious disadvantages arising from the formation of byproducts of the methylation reaction (viz. free acids derived from the methylating agents or correspond ing salts if acid binding agents have also been used) the separation of which from the desired quaternary ammonium salts is extremely difficult. If, however, a Water-soluble embonate is added to the crude reaction mixture in which any free acid has previously been neutralised and from which suspended or precipitated solids (if any) have been removed, the embonate corresponding to the. desired salt is precipitated and thereby isolated. After recrystallisation (which may conveniently be eifected from water) the embonate can then be converted into the desired salt by treatment with an acid containing the required anion. r The process of this invention is not only applicable to the production of known quaternary am monium salts of theaforesaid general type as a means for eliminating otherwise necessary purie fication steps but also renders possible the commercial production of hitherto unknown quaternary ammonium salts of the aforesaid general type that would be difficult to produce by the application of known methods. For example the quaternary ammonium salts containing a radical derived from an acid the anion of which is neither physiologically nor pharmacologically un- Thus, in general,

desirable, for example the bitartrates, bisulphates and dihydrogen phosphates are now rendered readily available. Other examples of new salts which can be conveniently prepared using the process of the present invention are adipates (neutral and acid), benzoates, carbonates, chlorides, citrates, acid maleates, methosulphates, succinates (neutral and acid), neutral sulphates and neutral tartrates.

The process of the present invention is illustrated by the following examples:

Example I Hexamethylene diamine (116 gms.), sodium carbonate (466 gms.), and water (800 mls.) were heated to 60 C., and dimethyl' sulphate (830 gms.) added with stirringv over 1 /2 hourskeep ing the temperature below 90 C. The reaction mixture Was then stirred at 90 C. for 2 hours,

then cooled to 20 C., acetone (1200 mls.) added and the whole cooled to C.

The solid formed was removed by' filtration and washed with acetone (150 mls.). Filtrate and washin s were diluted with water to 4.1itres and heated to 60 C. under'reflux. To this was added a solution prepared from embonic acid (388 gms.), sodium'hydroxide (80" gms.) and water (5 litres), the Whole refluxed for minutes 'The filtrate and washings were evaporated in a steam pan to a thick syrup which was granulated by stirringwith ethyl alcohol (1500 mls.). The ethyl alcohol was removed by filtration and hexamethylene 1:fi-bis trimethyl-ammonium bitarrtrate (400 gms.) was obtained as the monohydrate by recrystallisation from methyl alcohol (700 mls.) I

The embonic acid which is regenerated can; of course, be used for the next operation. Owing to its extreme insolubility, th loss is extremely small. 7

Example II The embonate (588 gms.) prepared by the process of Example I was dissolved in boiling water "(4 litres); Hydrobrornic acid w./w. (325 gms.) diluted with water (2' litres) was added slowly at the boil and the precipitated embom'c acid removed by filtering hot and washing twice with hot water (1 litre). The filtrate and washings were evaporated to dryness in a steam panand the residue recrystallised from ethyl alcohol (1200 mls.) to yield the dibromide (320 gms.) corresponding to the tartrate of Example I.

/ From an, aqueous solution obtained by the quaternation with the appropriate'alkyl halide of 1 :6-bis-dimethylaminohexane there was obtained in'analoguos manner to the embonate of Example I hexamethylene-l:G-bis-dimethylethylammonium embonate which crystallised from water as a hydrate and on drying gave an amorphous yellow powder M. P. 262-265 C. (with d'ecomp.).

*I claim: I r V 1; A compound of the general formula:

where R represents a member of the class consisting of methyl and ethyl and A represents the residue of 2 :2-dihydroxy-1 l-dinaphthylmethane-3z'3-dicarboxylic acid (embcnic acid).

2. Hexamethylene- 1:6 -bis-trimethylammoni.- um embonate.

3. Hexamethylene 1-: 6 '-'bis-dimethylethylammonium embonate.

HARRY JAMES BARBER.

References Cited in the file of this patent UNITED s ATEs PATENTS Number Name, Date 2,130,947 Carothers sept. 20, 1938 2,375,853 Kirby et al May 15,1945

OTHER REFERENCES Paton et al.: Nature. vol. 162, p. 810 (1948). 

1. A COMPOUND OF THE GENERAL FORMULA: 